P21 EFFECTIVENESS AND SAFETY OF DELAYED BORTEZOMIB, THALIDOMIDE AND DEXAMETHASONE (VTD) REGIMEN
Authors: V. Del Fabro, G. Schininà, G. Sapuppo, G. Uccello, M. Gentile, F. Palumbo, A. Romano, F. Di Raimondo, C. Conticello
Journal: HemaSphere (2023)

Bortezomib, thalidomide, and dexamethasone (VTD) plus autologous stem cell transplantation has been the standard treatment in Europe for transplant-eligible (TE) patients (pt) with newly diagnosed multiple myeloma (NDMM) until monoclonal antibody daratumumab has been added. Approval of the triplet comes from GIMEMA-MMY-3006 clinical trials (four 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; thalidomide 100 mg daily; dexamethasone 40 mg days 1 -4 and 9-12). However, some pt discontinue VTD because of severe adverse events (AE), despite its efficacy. In this real-life survey, we retrospectively evaluated the effectiveness and side effects of a delayed VTD regimen (dVTD) compared to standard VTD (sVTD) in TE NDMM patients. 74 pt were treated between 08/08/2016 and 31/07/2022 with VTD schema. sVTD was administered to 31 pt as in the trial (bortezomib on days 1-4-8-11). dVTD was administered to 43 pt with bortezomib on days 1, 8, 15 and 22 of 28-days cycles. Pt’ clinical characteristics are described in Table 1. In the sVTD group, 5 patients (16%) had one or more G3/G4 AE: among them 1 thrombocytopenia, 3 neutropenia and none G3/4 non-hematological AE. Hematological AE occurred in 50% of pt (N=15), and were anemia, thrombocytopenia and neutropenia. Six pt had G2/3 neutropenia (19.5%) resolved with granulocyte growth factors (GCSF). All cases of anemia were G1. One pt with thrombocytopenia needed transfusion. The rate of infections was 10% (N= 3) and included one case of G2 upper respiratory tract infection and two cases of G1 cystitis, resolved with antibiotic therapy. Peripheral neuropathy occurred in 10% of pt (N=3, 2 G1 cases and 1 G2) and skin changes (G1) in one case. In the dVTD group there were no G3/G4 AE. Hematological AE occurred in 9 pt (21%, G1-2). Anemia was found in 4 pt (9%, G2 only in one case, 2 cases treated with erythropoietin). Neutropenia occurred in 4 pt (9%), G2 only in one case treated with GCSF. G1 thrombocytopenia occurred in one pt (2,4%), peripheral neuropathy in 5 pt (12%), cutaneous rush in 4 pt (9%). None of pt belonging to dVTD or sVTD group had to discontinue treatment for toxicities. In sVTD group the responses after induction therapy were CR in 7 pt, VGPR in 16 pt, PR in 5 pt, PD in 3 pt with improvement after transplantation with 13 pt in CR, 10 pt in VGPR (Table 2). During follow up 12 pt progressed and underwent a second line treatment and 3 pt died for PD. In dVTD group the responses after induction therapy were CR in 6 pt, VGPR in 17 pt, PR in 17 pt, MR in 2 pt. After transplantation: 16 pt in CR, 18 pt in VGPR, 4 pt in PR, 1 pt in SD and 1 in PD. During follow up 14 pt progressed and underwent a second line treatment and 5 pt died for PD. Median PFS was 81 months in sVTD group ando not reached in dVTD (p=0.496). Median overall survival was 66 months for dVTD group and not reached for sVTD group (p=0.186). The current standard of care for NDMM pt is the combination of daratumumab with VTD. The schedule includes bortezomib on days 1-4-8-11 However, this schedule represents a discomfort for the patient mostrly for accesses to the hospital twice a week. Our findings suggest that delayed VTD is not inferior in safety and efficacy to standard VTD regimen. Using a delayed schema we achieved better patient compliance with a comparable toxicity profile, without worsening the efficacy and the survival curves. These data may support the use of the same schedule in combination with daratumumab. TABLE 1 - dVTd (43) sVTD (31) Age Median range male 41 - 70 43 - 72 Median range female 43-66 43-61 Gender Male, N (%) 22 (51%) 19 (61%) Female, N (%) 21 (49%) 12 (39%) Paraprotein (isotype) IgG-k 20 (46%) 9 (29%) IgG-L 9 (21%) 5 (16%) IgA-k 6 (14%) 2 (6.5%) IgA-L 1 (2%) 2 (6.5%) Macromolecular k 3 (7%) 7 (22.5%) Micromolecular lambda 3 (7%) 6 (19.5%) Others 2 (4%) 0 (0%) ISS stage at baseline I, N (%) 23 (53%) 5 (16%) II, N (%) 8 (19%) 15 (48.5%) III, N (%) 13 (30% 11 (35.5%) Cytogenetics risk High, N (%) 9 (21%) 6 (19.5%) Standard, N (%) 21 (49%) 20 (64.5%) Not Evaluable 13 (30%) 5 (16%) Creatinine clearance < 50 ml/min/m2 6 (14%) 9 (29%) >50 ml/min/m2 39 (86%) 22 (71%) Bone Lesions No one, N (%) 3 (7%) 8 (26%) More than 1, N (%) 40 (93%) 23 (74%) Extramedullary lesions Yes, N (%) 6 (14%) 6 (19.5%) No, N (%) 37 (86%) 25 (80.5%) Bone Marrow Involvement <60%, N (%) 28 (63%) 18 (58%) ≥60%, N (%) 8 (16%) 13 (42%) Missed, N (%) 7 (16%) 0 (0%) LDH Normal, N (%) 39 (90%) 27 (87%) Increased N (%) 4 (10%) 4 (13%)